tbuckley/cabot-search huggingface dataset:
Abstract 5011: Meta-analysis of human cancer single cell RNAseq datasets using the fully integrated IMMUcan database
Authors: Jordi Camps, Floriane Noel, Robin Liechti, Lou Goetz, Caroline Hoffmann, Lucile Massenet-Regad, Elise Amblard, Melissa Saichi, Mahmoud M. Ibrahim, Jack Pollard, Jasna Medvedovic, Helge G. Roider, Vassili Soumelis
Journal: Cancer Research (2022)

Abstract The development of single cell RNA-sequencing (scRNAseq) technologies has greatly contributed to deciphering the tumor microenvironment (TME) landscape, and a wealth of biological data is now publicly accessible. This represents a very valuable resource to researchers in the field, offering a reference for comparison of novel results, as well as opportunities for original meta-analysis studies. However, the massive amount of biological information renders its exploitation difficult in the absence of a well-structured and annotated resource. Marked heterogeneity and variability between studies in terms of cancer type, clinical context, technological platform, data quality, number and type of cells, create additional bottlenecks. We have developed a fully integrated scRNAseq database exclusively dedicated to human cancer. It gathers 134 datasets on 51 different cancer types, annotated in 50 fields containing precise clinical, technological and biological information. We developed an original data processing pipeline organized in 4 steps: first, data collection; second, data processing, which includes quality control, sample integration, cell clustering; third, cell ontology tree of the TME, built and used to annotate the clusters in a supervised and manual manner; and fourth, interface to analyze TME in a cancer type-specific or global manner. This integrated, accessible and user-friendly resource should be of great value to the biomedical community. It represents an unprecedented level of detailed annotation, offering vast possibilities for downstream exploitation of human cancer scRNAseq data for discovery and validation studies. The database is freely accessible at: https://immucanscdb.vital-it.ch. Citation Format: Jordi Camps, Floriane Noel, Robin Liechti, Lou Goetz, Caroline Hoffmann, Lucile Massenet-Regad, Elise Amblard, Melissa Saichi, Mahmoud M. Ibrahim, Jack Pollard, Jasna Medvedovic, Helge G. Roider, Vassili Soumelis. Meta-analysis of human cancer single cell RNAseq datasets using the fully integrated IMMUcan database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5011.
Prolonged Myocardial Regenerative Capacity in Neonatal Opossum
Authors: Chihiro Nishiyama, Yuichi Saito, Akane Sakaguchi, Mari Kaneko, Hiroshi Kiyonari, Yuqing Xu, Yuichiro Arima, Hideki Uosaki, Wataru Kimura
Journal: Circulation (2022)

Early neonates of both large and small mammals are able to regenerate the myocardium through cardiomyocyte proliferation for only a short period after birth. This myocardial regenerative capacity declines in parallel with withdrawal of cardiomyocytes from the cell cycle in the first few postnatal days. No mammalian species examined to date has been found capable of a meaningful regenerative response to myocardial injury later than 1 week after birth.We examined cardiomyocyte proliferation in neonates of the marsupial opossum (Monodelphis domestica) by immunostaining at various times after birth. The regenerative capacity of the postnatal opossum myocardium was assessed after either apex resection or induction of myocardial infarction at postnatal day 14 or 29, whereas that of the postnatal mouse myocardium was assessed after myocardial infarction at postnatal day 7. Bioinformatics data analysis, immunofluorescence staining, and pharmacological and genetic intervention were applied to determine the role of AMPK (5'-AMP-activated protein kinase) signaling in regulation of the mammalian cardiomyocyte cell cycle.Opossum neonates were found to manifest cardiomyocyte proliferation for at least 2 weeks after birth at a frequency similar to that apparent in early neonatal mice. Moreover, the opossum heart at postnatal day 14 showed substantial regenerative capacity both after apex resection and after myocardial infarction injury, whereas this capacity had diminished by postnatal day 29. Transcriptomic and immunofluorescence analyses indicated that AMPK signaling is activated in postnatal cardiomyocytes of both opossum and mouse. Pharmacological or genetic inhibition of AMPK signaling was sufficient to extend the postnatal window of cardiomyocyte proliferation in both mouse and opossum neonates as well as of cardiac regeneration in neonatal mice.The marsupial opossum maintains cardiomyocyte proliferation and a capacity for myocardial regeneration for at least 2 weeks after birth. As far as we are aware, this is the longest postnatal duration of such a capacity among mammals examined to date. AMPK signaling was implicated as an evolutionarily conserved regulator of mammalian postnatal cardiomyocyte proliferation.
Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy
Authors: Man-Fung Yuen, Jeong Heo, Hiromitsu Kumada, Fumitaka Suzuki, Yoshiyuki Suzuki, Qing Xie, Jidong Jia, Yoshiyasu Karino, Jinlin Hou, Kazuaki Chayama, Michio Imamura, Judy Y. Lao-Tan, Seng Gee Lim, Yasuhito Tanaka, Wen Xie, Jung-Hwan Yoon, Zhongping Duan, Masayuki Kurosaki, Sung-Jae Park, Madalinee Eternity Labio, Rajneesh Kumar, Young-Oh Kweon, Hyung Joon Yim, Yu Tao, Jennifer Cremer, Robert Elston, Matt Davies, Sharon Baptiste-Brown, Kelong Han, Fiona M. Campbell, Melanie Paff, Dickens Theodore
Journal: Journal of Hepatology (2022)
MRI lesions of the spine in patients with axial spondyloarthritis: an update of lesion definitions and validation by the ASAS MRI working group
Authors: Xenofon Baraliakos, Mikkel Østergaard, Robert GW Lambert, Iris Eshed, Pedro M Machado, Susanne Juhl Pedersen, Ulrich Weber, Manouk de Hooge, Joachim Sieper, Denis Poddubnyy, Martin Rudwaleit, Désirée van der Heijde, Robert BM Landewé, Walter P Maksymowych
Journal: Annals of the Rheumatic Diseases (2022)

Spinal MRI is used to visualise lesions associated with axial spondyloarthritis (axSpA). The ASAS MRI working group (WG) updated and validated the definitions for inflammatory and structural spinal lesions in the context of axSpA.
Abstract 1123: c-Met downregulation contributes to Metformin-induced inhibition of MDA-MB-468 triple negative breast cancer cells
Authors: Dana M. Gant, Zhikun Ma, Amanda B. Parris, Xiaohe Yang
Journal: Cancer Research (2022)

Abstract Triple negative breast cancer (TNBC) is the breast cancer subtype that is most refractory to treatment. Thus, identification of novel molecular targets and drug treatments are needed to improve prognosis for patients. The widely used anti-diabetic drug Metformin has been reported to possess anti-cancer properties. Although it is believed that Metformin may exert its anti-cancer effects through indirect reduction of glucose and insulin levels, and directly activating the AMPK kinase and inhibiting downstream cancer-related pathways, the molecular mechanisms underlying its anti-cancer function in TNBC have yet to be fully elucidated. In this study, we investigated the role and mechanism of Metformin-mediated downregulation of oncogenic c-Met in MDA-MB-468 TNBC cells. Our results demonstrated greater sensitivity of MDA-MB-468 cells to Metformin compared to other breast cancer cell lines. Metformin-induced inhibition of MDA-MB-468 cell proliferation was correlated with the downregulation of c-Met at both protein and mRNA levels. Overexpression of c-Met in MDA-MB-468 cells using a lentiviral vector system rendered the cells resistant to Metformin, which was accompanied by the promotion of cancer stem cell stemness. Functionally, we demonstrated that c-Met induced activation of receptor tyrosine kinase (RTK) signaling pathways play a critical role in c-Met-modulated Metformin responsiveness. These novel findings highlight c-Met as a key regulator of Metformin-mediated inhibition of TNBC cell growth, suggesting that c-Met overexpression may be a critical factor contributing to metformin resistance. To this end, combination of Metformin with c-Met inhibitors could be a useful strategy to improve Metformin-mediated anti-cancer efficacies in TNBC. Citation Format: Dana M. Gant, Zhikun Ma, Amanda B. Parris, Xiaohe Yang. c-Met downregulation contributes to Metformin-induced inhibition of MDA-MB-468 triple negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1123.
Low dose, add-on prednisolone in patients with rheumatoid arthritis aged 65+: the pragmatic randomised, double-blind placebo-controlled GLORIA trial
Authors: Maarten Boers, Linda Hartman, Daniela Opris-Belinski, Reinhard Bos, Marc R Kok, Jose AP Da Silva, Eduard N Griep, Ruth Klaasen, Cornelia F Allaart, Paul Baudoin, Hennie G Raterman, Zoltan Szekanecz, Frank Buttgereit, Pavol Masaryk, L Thomas Klausch, Sabrina Paolino, Annemarie M Schilder, Willem F Lems, Maurizio Cutolo
Journal: Annals of the Rheumatic Diseases (2022)

Background Low-dose glucocorticoid (GC) therapy is widely used in rheumatoid arthritis (RA) but the balance of benefit and harm is still unclear. Methods The GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) pragmatic double-blind randomised trial compared 2 years of prednisolone, 5 mg/day, to placebo in patients aged 65+ with active RA. We allowed all cotreatments except long-term open label GC and minimised exclusion criteria, tailored to seniors. Benefit outcomes included disease activity (disease activity score; DAS28, coprimary) and joint damage (Sharp/van der Heijde, secondary). The other coprimary outcome was harm, expressed as the proportion of patients with ≥1 adverse event (AE) of special interest. Such events comprised serious events, GC-specific events and those causing study discontinuation. Longitudinal models analysed the data, with one-sided testing and 95% confidence limits (95% CL). Results We randomised 451 patients with established RA and mean 2.1 comorbidities, age 72, disease duration 11 years and DAS28 4.5. 79% were on disease-modifying treatment, including 14% on biologics. 63% prednisolone versus 61% placebo patients completed the trial. Discontinuations were for AE (both, 14%), active disease (3 vs 4%) and for other (including covid pandemic-related disease) reasons (19 vs 21%); mean time in study was 19 months. Disease activity was 0.37 points lower on prednisolone (95% CL 0.23, p&lt;0.0001); joint damage progression was 1.7 points lower (95% CL 0.7, p=0.003). 60% versus 49% of patients experienced the harm outcome, adjusted relative risk 1.24 (95% CL 1.04, p=0.02), with the largest contrast in (mostly non-severe) infections. Other GC-specific events were rare. Conclusion Add-on low-dose prednisolone has beneficial long-term effects in senior patients with established RA, with a trade-off of 24% increase in patients with mostly non-severe AE; this suggests a favourable balance of benefit and harm. Trial registration number NCT02585258 .
Abstract 1035: VCP/p97 promotes pancreatic cancer growth by enhancing mutant p53 activity
Authors: Jieqiong Wang
Journal: Cancer Research (2022)

Abstract Pancreatic cancer is the most lethal malignant neoplasms across the world with the lowest overall five-year survival rate (9%). TP53 is mutated in ~70% of pancreatic ductal adenocarcinomas (PDACs). Hotspot p53 mutants promote cancer cell proliferation, metastasis and metabolism through their gain-of-function (GOF). Among the p53 “hotspot” mutations, R273 is the most frequent mutation position (~12%) with R273H as the most commonly mutated codon (~8%) in PDACs. However, the mechanisms underlying regulation of mutant p53s’ GOF in PDACs remain incompletely understood. In our attempt to address this question, we recently identified the ATPase valosin-containing protein (VCP)/p97 as a novel mutant p53-binding protein by performing immunoprecipitation (IP)-tandem mass spectrometry (LC-MS/MS) analysis. VCP bound to p53-R273H via the DNA-binding domain. VCP inhibition either by genetic depletion or pharmacological inhibition by CB-5083 resulted in the increase of MDM2-mediated ubiquitination and degradation of p53-R273H. VCP did so by binding to MDM2 and disturbing its interaction with mutant p53. As a result, VCP protected mutant p53 from degradation and enhanced its GOF in cancer development. Ablation of VCP retarded PDAC cell growth in vitro and in vivo. Our further studies also unveiled the negative regulation of wt p53 by VCP in cancer cells. Together, these results demonstrate that VCP can strengthen mutant p53’s oncogenic function by stabilizing it and negating wt p53 function, suggesting VCP as a resistant factor for chemotherapy against PDACs and thus a potential therapeutic target of the mutant p53-harboring pancreatic cancers as well as of the wt p53-containing cancer cells. Citation Format: Jieqiong Wang. VCP/p97 promotes pancreatic cancer growth by enhancing mutant p53 activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1035.
Abstract 2148: Pre-clinical models recapitulating the spectrum of response of BRCA associated pancreatic cancer
Authors: Talia Golan, Chani Stossel, Maria Raitses-Gurevitch, Dikla Atias, Tamar Beller, Steven Gallinger, Raanan Berger
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease, with the majority of patients diagnosed at an advanced stage. Comprehensive genomic analysis identified the homologous recombination deficiency (HRD) subgroup which is predominantly enriched in patients harboring germline BRCA1/2 mutations (glBRCA) and presents ~7% and up to 15% in selected high-risk populations. Tumors with HRD are susceptible to DNA-damaging agents and PARP inhibition. However, not all patients demonstrate a similar response, and a spectrum is observed. We analyzed the clinical outcome of ninety-one glBRCA PDAC patients treated at Sheba Medical Center. We identify three main subgroups of response spanning from ~25% patients refractory to first line platinum agents and ~9% patients with durable long-term response with no evidence of disease for over three years. The majority of the patients display a prolonged response to platinum and PARPi maintenance (&amp;gt;24 months) followed by acquired resistance. We generated patient derived xenograft (PDX) models and an ex-vivo culture system (EVOC) from naïve to treatment tissue and at clinical resistance. In vivo efficacy to platinum agents and PARPi demonstrates that these models recapitulate the specific clinical spectrum of response. We demonstrate the utility of both pre-clinical models in their ability to predict response to platinum-based agents and PARPi, with EVOC having a potential to assist in medical decisions while treating the patient. Whole genome sequencing of the tumors revealed that BRCA monoallelic tumors are associated with innate resistance while biallelic tumors reflect sensitivity to platinum agents and PARPi. In the acquired resistance models, the main identified mechanism of resistance was due to reversion mutations in 4/6 of samples. Whole genome analysis demonstrates high mutational and neo-antigen load in majority of the glBRCA tumors. In a preliminary study, we show the efficacy of anti PD1 in a novel humanized glBRCA PDAC PDX model. This extensive preclinical and clinical collection of BRCA associated PDAC, enables further understanding and investigation of this unique subtype in aim to develop alternative treatments to overcome resistance. Citation Format: Talia Golan, Chani Stossel, Maria Raitses-Gurevitch, Dikla Atias, Tamar Beller, Steven Gallinger, Raanan Berger. Pre-clinical models recapitulating the spectrum of response of BRCA associated pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2148.
Abstract 859: Characterizing <i>SMARCA4/STK11/KEAP1</i> co-mutant lung adenocarcinoma
Authors: Emily Costa, Corrin Wohlheiter, Samuel Tischfield, Alister Funnell, JT Poirier, Álvaro Quintanal Villalonga, Triparna Sen, Charles Rudin
Journal: Cancer Research (2022)

Abstract Lung adenocarcinoma (LUAD), constituting 50% of non-small cell lung cancer, is classically defined by the presence of driver mutations in oncogenes such as KRAS, EGFR, and BRAF. While the development of driver-targeted therapies has significantly improved survival in subsets of patients with LUAD, studies examining tumor sequencing data and clinical outcomes have shown that intra-driver genetic and phenotypic heterogeneity underlie differential patient responses to these therapies. In particular, co-occurring alterations in the genes SMARCA4 (BRG1), STK11 (LKB1), and KEAP1 are predictive of exceptionally poor prognosis and worse overall survival in metastatic LUAD patients. SMARCA4 loss is also a hallmark of undifferentiated, highly chemoresistant NSCLC tumors. While these co-mutations most often appear in KRAS-driven tumors, their association with poor outcomes is maintained regardless of driver status. Studies exploring the molecular features of SMARCA4-deficient and STK11/KEAP1 co-mutant LUAD have yielded translational insights specific to these subsets, establishing a rationale to characterize the unique biology of SMARCA4/STK11/KEAP1 (BLK) triple-mutant LUAD. To this end, we are profiling BLK LUAD through a combination of genomic, transcriptomic, epigenomic, and phenotypic assays in in vitro models. We have generated paired isogenic in vitro models of BLK LUAD via CRISPR-Cas9 knockout. Phenotypic analyses of these cell lines, whose engineered genotypes model varying combinations of SMARCA4, KEAP1, and STK11 loss, have revealed growth rate differences in vitro, and pairwise comparisons of RNA-sequencing in these lines show downregulation of lung differentiation markers and upregulation of metastasis-associated genes concomitant with SMARCA4 loss. In conclusion, we have generated isogenic preclinical models showing molecular and phenotypic features consistent with observations reported in BLK LUADs. Further molecular and functional characterization of these models may reveal mechanistic insights into the biology of this subset of aggressive tumors. Citation Format: Emily Costa, Corrin Wohlheiter, Samuel Tischfield, Alister Funnell, JT Poirier, Álvaro Quintanal Villalonga, Triparna Sen, Charles Rudin. Characterizing SMARCA4/STK11/KEAP1 co-mutant lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 859.
Abstract 2767: Low baseline serum IFNg and TNFa are predictive of response to bexmarilimab
Authors: Jussi Koivunen, Juho Jalkanen, Mari Björkman, Jami Mandelin, Petri Bono
Journal: Cancer Research (2022)

Abstract Introduction: Bexmarilimab is a novel macrophage re-programming agent targeting CLEVER-1 on tumor associated macrophages. CLEVER-1 is a highly immunosuppressive macrophage scavenger receptor. Inhibition of CLEVER-1 has been shown remove T cell exhaustion, induce clonal expansion of cytotoxic CD8 cells, and improve their infiltration into the tumor. Recently in a first-in-human Phase I/II study named MATINS (NCT03733990) bexmarilimab was reported to have a survival benefit in 30% of patients with advanced gastric cancer, cutaneous melanoma and cholangiocarcinoma as a single agent (ESMO 2021). Methods &amp; Aims: As a part of the mode of action of bexmarilimab, it is known to induce TNFa and IFNg responses, especially when IFNg levels are low. Using ROC analysis we aimed to test the performance of baseline cytokine serum IFNg and TNFa levels to identify patients that experienced a survival benefit from bexmarilimab compared to patients that did not benefit from bexmarilimab. Results: 30 patients, 10 per each tumor type, were treated with bexmarilimab at 1mg/kg Q3W. Mean age 59 years (SD, 9 years), 73% male, with an average of 3 previous lines of therapy, median survival not yet reached. At baseline, patients that saw a clinical benefit (CBR) from bexmarilimab had average serum IFNg levels of 5.11 pg/ml (SD, +/- 4.99 pg/ml) compared to 13.07 pg/ml (SD, +/- 13.26) in patients that did not respond to the treatment. Similarly serum TNFa levels 0.96 pg/ml (SD, +/- 0.74 pg/ml) in patients that benefited from bexmarilimab compared to 2.37 pg/ml (SD, +/- 1.43 pg/ml) in patients that did not respond to the treatment. Log transformed values were used for ROC analyses. Used together IFNg and TNFa performed well to identify patients that are responsive to bexmarilimab (AUC 0.83, P &amp;lt; 0.0001). Conclusion: Bexmarilimab works well in patients with low IFNg and TNFa levels, which is opposite to what is usually seen with checkpoint inhibitors and other T cell activating agents. Citation Format: Jussi Koivunen, Juho Jalkanen, Mari Björkman, Jami Mandelin, Petri Bono. Low baseline serum IFNg and TNFa are predictive of response to bexmarilimab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2767.
Abstract 804: Trapped PARP1 cytotoxicity is modulated by the ubiquitin-dependentsegregase p97
Authors: Dragomir B. Krastev, Chris Lord
Journal: Cancer Research (2022)

Abstract Poly-(ADP-ribose) polymerase inhibitors (PARPi) elicit anti-tumor activity in homologous recombination defective cancers by promoting cytotoxic, chromatin-bound, “trapped” PARP1. Here we have elucidated a pathway that process trapped PARP1. By exploiting wild-type or trapping-resistant PARP1 transgenes combined with either a rapid immunoprecipitation mass-spectrometry of endogenous proteins (RIME)-based approach or PARP1 Apex2-proximity labelling linked to mass-spectrometry, we generated proteomic profiles of trapped and non-trapped PARP1 complexes. These experiments demonstrated an increase in the SUMO1/2 modifications upon trapping, as well as an interaction with the ubiquitin-regulated p97 ATPase (aka VCP). Subsequent experiments demonstrated that upon trapping, PARP1 is SUMOylated by the SUMO-ligase PIAS4 and subsequently ubiquitinated by the SUMO-targeted E3-ubiquitin ligase, RNF4, events that promote p97 recruitment and p97 ATPase-mediated removal of trapped-PARP1 from chromatin. Consistently, small molecule p97 complex inhibitors, including a metabolite of the clinically-used drug disulfiram, CuET that acts as a p97 sequestration agent, prolong PARP1 trapping and thus enhance PARPi-induced cytotoxicity in homologous recombination defective tumor cells and patient-derived tumor organoids. Taken together, these results suggest that p97 ATPase plays a key role in the processing of trapped PARP1 from chromatin and the response of homologous recombination defective tumor cells to PARPi. Citation Format: Dragomir B. Krastev, Chris Lord. Trapped PARP1 cytotoxicity is modulated by the ubiquitin-dependentsegregase p97 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 804.